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Objective:To investigate the clinical features of patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations,and the treatment outcomes of EGFR tyrosine kinase inhibitors (TKIs) in these patients.Methods:We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College and Beijing Hospital from January 2010 to December 2015,including 40 advanced patients who received EGFR-TKI.Results:Among the total 128 patients,11 patients were non-adenocarcinoma,including squamous carcinoma (3.9％),adenosquamous carcinoma (2.3 ％),large cell carcinoma (0.8％),and composite neuroendocrine carcinoma (1.6％).Single mutations accounted for 75.0％ (96/128),including G719X (29.7％),S768I (18.0％),20 exon insertion (13.3％),L861Q (12.5％),De novo T790M (0.8％),and T725 (0.8％).Thirty-two patients harbored complex mutations.Forty advanced patients received EGFR-TKI,the objective response rate (ORR) was 20.0％,the disease control rate (DCR) was 85.0％,and the progression-free survival (PFS) was 6.4 [95％ confidence interval (95％ CI),4.8-7.9] months.The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861Q subtypes showed that ORR was 21.2％ (7/33),the DCR was 93.9％ (31/33),and PFS was 7.6 (95％ CI,5.8-9.4) months.Patients with exon 20 insertion mutation and De novo T790M experienced rapid disease progression with PFS no more than 2.7 months.Conclusions:Uncommon EGFR-mutant NSCLCs are heterogeneous,EGFR-TKIs can have different efficacy in this specific subtype,and thus further individual assessment is required for each case.